Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A 2-Year Follow-up Study.
The intra-articular injection of mesenchymal stem cells (MSCs) into the knee has shown a potential for the treatment of generalized cartilage loss in osteoarthritis (OA). However, there have been few midterm reports with clinical and structural outcomes. To assess the midterm safety and efficacy of an intra-articular injection of autologous adipose tissue-derived (AD) MSCs for knee OA at 2-year follow-up. Cohort study; Level of evidence, 3. Eighteen patients with OA of the knee were enrolled (3 male, 15 female; mean age, 61.8 ± 6.6 years [range, 52-72 years]). Patients in the low-, medium-, and high-dose groups received an intra-articular injection of 1.0 × 107, 5.0 × 107, and 1.0 × 108 AD MSCs into the knee, respectively. Clinical and structural evaluations were performed with widely used methodologies including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and measurements of the size and depth of the cartilage defect, signal intensity of regenerated cartilage, and cartilage volume using magnetic resonance imaging (MRI). There were no treatment-related adverse events during the 2-year period. An intra-articular injection of autologous AD MSCs improved knee function, as measured with the WOMAC, Knee Society clinical rating system (KSS), and Knee injury and Osteoarthritis Outcome Score (KOOS), and reduced knee pain, as measured with the visual analog scale (VAS), for up to 2 years regardless of the cell dosage. However, statistical significance was found mainly in the high-dose group. Clinical outcomes tended to deteriorate after 1 year in the low- and medium-dose groups, whereas those in the high-dose group plateaued until 2 years. The structural outcomes evaluated with MRI also showed similar trends. This study identified the safety and efficacy of an intra-articular injection of AD MSCs into the OA knee over 2 years, encouraging a larger randomized clinical trial. However, this study also showed potential concerns about the durability of clinical and structural outcomes, suggesting the need for further studies. NCT01300598.


The homeodomain protein Pbx1 is involved in cAMP-dependent transcription of human CYP17.
Pbx1 is a homeodomain transcription factor involved in cAMP-dependent transcriptional regulation of the bovine CYP17 gene. In this study, we have investigated the involvement of Pbx1 in the transcriptional regulation of the human CYP17 gene. Although a sequence identical to previously determined Pbx-binding sites is not present in the promoter region of the human CYP17 gene, three putative Pbx-binding sites are identified by sequence similarity analysis. Coexpression of Pbx1 and a catalytic subunit of protein kinase A (PKA) greatly enhances reporter gene transcription via the 5'-flanking region of the human CYP17 gene. Upon gel shift analysis utilizing nuclear extracts from human adrenal H295R cells, one of the three putative Pbx1-binding sites, -250/-241 bp, shows the typical intense doublet observed with other Pbx-binding sites. 5'-Deletion analyses of the reporter construct containing this Pbx-binding site showed approximately sixfold induction by coexpression of Pbx1 and PKA compared to the basal transcription, suggesting that Pbx1 binds the -250/-241 bp sequence and participates in cAMP-dependent regulation of the human CYP17 gene.


Multiple Acute Infection by Anisakis: A Case Series.
The ingestion of raw seafood infected with nematode larvae of the Anisakidae family can lead to gastric anisakiasis. The majority of the infections involve a single larva, however, there have been instances of multiple infection. The incidence rate and the characteristics of multiple infection by Anisakis remain poorly understood. We herein present a case of parasitization by multiple Anisakis larvae and describe 14 cases of multiple parasitization representing the largest reported case series to date. Endoscopists should therefore be aware of the potential for multiple infection by Anisakis and the need for a thorough inspection of all parts of the stomach when encountering such cases.


Epidemiology in the workplace: the problem of misclassification.
Strategies for recognition and quantification of misclassification are presented. Misclassification occurs when a subject is placed in the wrong "exposure" or the wrong "outcome" category as a result of the failure of an index measurement to reflect exposure or disease accurately. Data from a Health Hazard Evaluation illustrate how misclassification may result in an unwarranted etiologic assumption. Data from a lung cancer screening program illustrate how misclassification may result in erroneous estimates of disease prevalence.


Effective in-vivo utilization of lipid-based nanoparticles as drug carrier for carvedilol phosphate.
Lipid nanoparticles as carrier for oral drug administration improve gastrointestinal solubility of poorly soluble drugs and thus enhance bioavailability. However, basic drugs may undergo rapid dissolution from such solid dispersions in the stomach and precipitate in the intestine due to their higher solubility in acidic medium. Therefore, the objective of this work was to study the enhancement in bioavailability of carvedilol phosphate (basic drug) by providing an alkaline gastric environment to drug-loaded solid lipid nanoparticles. An alkaline gastric environment in rats was created and maintained with oral administration of an antacid suspension 5 min before and 30 min post dosing. The formulation administered orally exhibited enhanced bioavailability (∼27%) when compared with drug suspension and sustained release behaviour when compared with formulation under ideal gastric conditions. The enhanced bioavailability is due to the presence of lipid nanoparticles as drug carrier while the sustained-release characteristic may be attributed to the presence of antacid, which resulted in elevation of gastric pH and reduced the drug's solubility. It may be concluded that although lipid nanoparticles can be instrumental in improving bioavailability, additional sustained release may be achieved by targeting intestinal release of basic drugs from lipid vehicles, which is possible by incorporating them into suitable enteric-coated formulations.


Snail: More than EMT.
Snail has moved into the fast lane of development and cancer biology with the epithelial-mesenchymal transition (EMT) emerging as one of the hottest topics in medical science within the past few years. Snail not only acts primarily as a key inducer of EMT but also plays an important role in cell survival, immune regulation and stem cell biology. This review focuses on the regulation of Snail and discusses the EMT-dependent and -independent functions of Snail in development and disease. Understanding the regulation and functional roles of Snail will shed new light on the mechanism of tumor progression and the development of novel cancer therapies.


Update: influenza activity--United States, August 30, 2009-January 9, 2010.
The emergence and spread of the 2009 pandemic influenza A (H1N1) virus (2009 H1N1) resulted in extraordinary influenza activity in the United States throughout the summer and fall months of 2009. During this period, influenza activity reached its highest level in the week ending October 24, 2009, with 49 of 50 states reporting geographically widespread disease. As of January 9, 2010, overall influenza activity had declined substantially. Since April 2009, the dominant circulating influenza virus in the United States has been 2009 H1N1. This report summarizes U.S. influenza activity from August 30, 2009, through January 9, 2010.


Multi-view information fusion using multi-view variational autoencoder to predict proximal femoral fracture load.
Hip fracture occurs when an applied force exceeds the force that the proximal femur can support (the fracture load or "strength") and can have devastating consequences with poor functional outcomes. Proximal femoral strengths for specific loading conditions can be computed by subject-specific finite element analysis (FEA) using quantitative computerized tomography (QCT) images. However, the radiation and availability of QCT limit its clinical usability. Alternative low-dose and widely available measurements, such as dual energy X-ray absorptiometry (DXA) and genetic factors, would be preferable for bone strength assessment. The aim of this paper is to design a deep learning-based model to predict proximal femoral strength using multi-view information fusion. We developed new models using multi-view variational autoencoder (MVAE) for feature representation learning and a product of expert (PoE) model for multi-view information fusion. We applied the proposed models to an in-house Louisiana Osteoporosis Study (LOS) cohort with 931 male subjects, including 345 African Americans and 586 Caucasians. We performed genome-wide association studies (GWAS) to select 256 genetic variants with the lowest p-values for each proximal femoral strength and integrated whole genome sequence (WGS) features and DXA-derived imaging features to predict proximal femoral strength. The best prediction model for fall fracture load was acquired by integrating WGS features and DXA-derived imaging features. The designed models achieved the mean absolute percentage error of 18.04%, 6.84% and 7.95% for predicting proximal femoral fracture loads using linear models of fall loading, nonlinear models of fall loading, and nonlinear models of stance loading, respectively. The proposed models are capable of predicting proximal femoral strength using WGS features and DXA-derived imaging features. Though this tool is not a substitute for predicting FEA using QCT images, it would make improved assessment of hip fracture risk more widely available while avoiding the increased radiation exposure from QCT.


Nebulized iloprost and noninvasive respiratory support for impending hypoxaemic respiratory failure in formerly preterm infants: a case series.
To describe a series of ex-preterm infants admitted to pediatric intensive care unit due to impending hypoxaemic respiratory failure complicated by pulmonary hypertension (PH) who were treated electively combining noninvasive ventilation (NIV) and nebulized iloprost (nebILO). Open uncontrolled observational study. Pediatric Intensive Care Unit, University Hospital. Ten formerly preterm infants with impending hypoxaemic respiratory failure and PH, of whom eight had moderate to severe bronchopulmonary dysplasia. Median age and body weight were 6.0 (2.75-9.50) months and 4.85 (3.32-7.07) kg, respectively. We observed a significant early oxygenation improvement in terms of PaO(2) /FiO(2) increase (P = 0.001) and respiratory rate reduction (P = 0.01). Hemodynamic also improved, as shown by heart rate (P = 0.002) and pulmonary arterial pressure systolic/systolic systemic pressure (PAPs/SSP) ratio reduction (P = 0.0137). NebILO was successfully weaned in positive response cases: 4 infants were discharged on oral sildenafil. Three patients failed noninvasive modality and needed invasive mechanical ventilation; hypoxic-hypercarbic patients were most likely to fail noninvasive approach. Only one patient requiring invasive ventilation died and surviving babies had a satisfactory 1-month post-discharge follow-up. CONCLUSIONS.: The noninvasive approach combining NIV and nebILO for ex-preterm babies with impending respiratory failure and PH resulted to be feasible and quickly achieved significant oxygenation and hemodynamic improvements.


Toe blood pressure by photoplethysmography: an index of healing in forefoot amputation.
The relative merits of toe systolic blood pressure and ankle systolic pressure in predicting the result of forefoot amputation were evaluated in 30 limbs of 27 patients who underwent digit or transmetatarsal amputation. Twenty-four (89%) patients were diabetic. An infrared photoplethysmograph placed distal to a pneumatic digit occluding cuff allowed rapid, simple preoperative assessment of toe systolic pressures. Ankle pressures was measured by Doppler ultrasound. Twenty (67%) amputations healed primarily, whereas 10 ultimately required reamputation at the below-knee level. The mean ankle pressure of limbs with healing of forefoot amputation, 136 +/- 39 mm Hg (+/- SD), did not differ significantly from those that failed to heal, 121 +/- 72 mm Hg (P greater than 0.4). Failure of an amputation to heal occurred in association with ankle pressures ranging from 60 to over 300 mm Hg. The mean value of toe pressures associated with healing of forefoot amputation, 86 +/- 39 mm Hg, was significantly higher than those not healing, 25 +/- 18 mm Hg (P less than 0.001). Failure of a forefoot amputation to heal occurred in all eight limbs with toe pressures less than 45 mm Hg, and in two of eight (25%) limbs with toe pressure between 45 and 55 mm Hg. Primary healing occurred in all 14 limbs with toe pressures greater than 55 mm Hg. These data suggest that toe pressure measurement may be a useful hemodynamic correlate of the healing potential of a forefoot amputation.


GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice.
Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR (Gipr-/- BM) and GIPR/S100A8/A9 (Gipr-/- /S100a9-/- BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing Giprfl/fl mice and Lyz2cre/+ mice (LysMΔGipr ). Under both short and progressive HFD regimens, Gipr-/- BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3+ regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr-/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysMΔGipr mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity.


[Breath tests as a noninvasive diagnostic method in Helicobacter pylori infection].
There are several diagnostic methods for Helicobacter pylori infection, some of them need an endoscopic procedure and biopsy to be performed (invasive) like the rapid urease test, culture and histology. Recently non invasive, specific, sensible, easy to perform and patient's well accepted methods had been developed known as breath test, based on the hydrolysis of labelled urea by Helicobacter pylori urease enzyme, to release ammonia and bicarbonate. Labelled CO2 reaches the bloodstream and the lungs, from where can be collected into the breath for quantification. Labelled urea has to options: 13C stable, non-radioactive and 14C unstable, radioactive. Breath test with 13C is based on the atomic mass difference between 12C and 13C and it is necessary a mass spectrometer and 40 minutes to perform it. Breath test with 14C has 1 uCi (one micro-curie) of radioactivity (1/300 of total radiation received in one year from the environment); the test takes 10 minutes and the samples are read in a beta counter. Both non-invasive tests had demonstrated sensitivity and specificity comparable to established "gold standards" for Helicobacter pylori infection diagnosis.


Cutting edge: cell surface linker for activation of T cells is recruited to microclusters and is active in signaling.
A controversy has recently emerged regarding the location of the cellular pool of the adapter linker for activation of T cells (LAT) that participates in propagation of signals downstream of the TCR. In one model phosphorylation and direct recruitment of cell surface LAT to activation-induced microclusters is critical for T cell activation, whereas in the other model vesicular, but not surface, LAT participates in these processes. By using a chimeric version of LAT that can be tracked via an extracellular domain, we provide evidence that LAT located at the cell surface can be recruited efficiently to activation-induced microclusters within seconds of TCR engagement. Importantly, we also demonstrate that this pool of LAT at the plasma membrane is rapidly phosphorylated. Our results provide support for the model in which the cell utilizes LAT from the cell surface for rapid responses to TCR stimulation.


Interleukin-1 beta activates c-jun NH2-terminal kinase subgroup of mitogen-activated protein kinases in mesangial cells.
We investigated whether JNK is activated by interleukin-1 beta (IL-1 beta) in mesangial cells. We performed in-gel kinase assays with His-c-jun-(1-79), which contains the amino-terminal activation domain of c-jun and a mutant His-c-jun in which Ser-63 and Ser-73 of His-c-jun were mutated to Ala as the substrates. JNK1 (p45) and JNK2 (p54) isoforms phosphorylated His-c-jun in mesangial cells. IL-1 beta produced a time- and concentration-dependent increase in JNK activity. IL-1 beta did not phosphorylated the mutant, His-c-jun. The IL-1 beta-activated JNK activity was independent of serum and suppressed by neither tyrosine kinase inhibitors nor protein kinase C inhibitors. JNK was also stimulated by anisomycin and okadaic acid but not by phorbol 12-myristate 13-acetate. The protein synthesis inhibitors and okadaic acid potentiated the IL-1 beta-induced JNK activity. Together, these studies indicate that the novel JNK group of protein kinases may play an important role in the signal transduction pathway initiated by proinflammatory cytokines, such as IL-1 beta in mesangial cells.


Consumer awareness and self-reported behaviours related to salt consumption in Australia.
Australians are eating far more salt than is good for health. In May 2007, the Australian Division of World Action on Salt and Health (AWASH) launched a campaign to reduce population salt intake. A consumer survey was commissioned to quantify baseline aspects of awareness and behaviour related to salt and health amongst Australians. A total of 1084 individuals aged 14 years or over were surveyed by ACA Research using an established consumer panel. Participants were selected to include people of each sex, within different age bands, from major metropolitan and other areas of all Australian states and territories. Participants were invited via email to complete a brief questionnaire online. Two-thirds knew that salt was bad for health but only 14% knew the recommended maximum daily intake. Seventy percent correctly identified that most dietary salt comes from processed foods but only a quarter regularly checked food labels for salt content. Even fewer reported their food purchases were influenced by the salt level indicated (21%). The survey showed a moderate understanding of how salt effects health but there was little evidence of action to reduce salt intake. Consumer education will be one part of the effort necessary to reduce salt intake in Australia and will require government investment in a targeted campaign to achieve improvements in knowledge and behaviours.


PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans.
The α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans. PET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (V T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed. In the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM V T. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm3 in cerebellum to 25.9 ± 2.9 mL/cm3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%. These results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.


Utilization of different soy products as affected by age in chicks.
Two experiments were conducted to evaluate the utilization of several different soy products at different ages in New Hampshire x Columbian male chicks. Six pens of eight chicks were fed dextrose-protein source diets (23% CP) containing 1 of 10 different protein sources from 0 to 21 d of age. Excreta were collected at 0 to 2, 3 to 4, 7, 14, and 21 d of age, and AMEn and amino acid (AA) digestibility were determined using acid-insoluble ash as a marker. Protein sources evaluated were as follows: Experiment 1--casein, soybean meal (SBM), soy protein concentrate (SPC), and soy protein isolate (SPI); Experiment 2-raw soyflakes, SBM, Williams 82 soybeans, heated Williams 82 soybeans, Kunitz-free soybeans (reduced trypsin inhibitor), lectin-free soybeans, and Kunitz/lectin-free soybeans. In Experiment 1, when comparing the MEn and AA digestibility values among diets at the same age, the ranking (from highest to lowest) for the four diets was casein, SPI, SPC, SBM. The MEn values increased (P < 0.05) with age for all four diets, with the increase being much smaller for the casein diet (3%) than the soy diets (mean increase of 13%). In Experiment 2, the SBM diet yielded the highest (P < 0.05) growth performance, MEn and AA digestibility values. The MEn and AA digestibility values of the Williams 82 soybeans, Kunitz-free soybeans, and lectin-free soybeans diets were much lower than those for the SBM diet. In general, the Kunitz/lectin-free soybeans yielded higher growth performance and MEn values than the Williams 82 soybeans, Kunitz-free soybeans, and lectin-free soybeans. The MEn values increased with age for most diets, and AA digestibility increased with age for the soyflake and Kunitz/ lectin-free soybean diets. Our results suggest there may be some potential benefits of feeding SPC or SPI during the first 1 to 3 wk posthatching and that underprocessed (under heated) soybeans should not be included in the diets of very young chicks.


A simplified domain structure of the burn-specific health scale-brief (BSHS-B): a tool to improve its value in routine clinical work.
Injury-specific instruments with good psychometric properties are valuable in the assessment of health status after trauma. Previous studies of burn-specific health have attempted to create broad domains such as physical and psychological health, but these domains have not been validated. In this study, burn-specific health domains were explored and validated by a factor analytic approach. Participants were 334 former burn patients injured between 1980 and 2000. Data were collected from medical charts and by a postal questionnaire, the Burn Specific Health Scale-Brief (BSHS-B). The nine subscales of the BSHS-B were subjected to second-order factor analysis. The sample was split into two subsamples that were equal with respect to burn severity. The factor structure was well replicated in each of the subsamples and in the total sample. Three internally consistent and well separated domains were derived: affect and relations (BSHS-B subscales interpersonal relationships, affect, sexuality), function (simple abilities, hand function), and skin involvement (heat sensitivity, treatment regimens, body image). The work subscale of the BSHS-B was excluded from the analysis because of consistent double loadings. The three domains had intelligible associations with injury-specific and sociodemographic variables. The underlying structure of the BSHS-B comprises three clinically meaningful health domains. The work subscale is not part of these domains and can be considered a separate outcome domain. The domain scores increase the understanding of outcome after burn injury and could prove useful in clinical use of the BSHS-B.


Bridging intragroup processes and intergroup relations: needing the twain to meet.
Despite their shared focus on groups, research bridging intragroup processes and intergroup relations is surprisingly rare. The goal of the present article is to highlight how understanding the reciprocal relationship between intragroup processes and intergroup relations offers valuable new insights into both topics and suggests new, productive avenues for research and theory development - particularly for understanding and improving intergroup relations. The article next briefly reviews key findings from three dominant frameworks in the field of intergroup relations: social cognition, social identity, and functional relations. It then discusses the complementary role of intergroup and intragroup dynamics, reviewing how intergroup relations can affect intragroup processes and then discussing how intragroup dynamics can shape intergroup relations. The final section considers the implications, theoretical and practical, of the proposed reciprocal relationships between intragroup and intergroup processes.


Isoprinosine (inosine pranobex BAN, INPX) in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.
The immunopharmacologic effects of Isoprinosine (INPX) have been associated with clinical benefit to the patient in a number of conditions characterized by immunodeficiency of diverse etiology. Immunodepressed homosexuals at risk of developing acquired immunodeficiency syndrome (AIDS) treated with placebo or INPX experienced an increase in the function and number of immunocompetent cells associated with clinical improvement. A multicenter trial designed to confirm these results has demonstrated that INPX produced an increase in natural killer (NK)-cell activity, total T cells, and T-helper cells, with certain effects persisting for months after completion of the 28-day treatment period. INPX-treated patients also experienced clinical improvement and decreased incidence of progression to AIDS. The administration of INPX for longer periods to patients with frank AIDS under a compassionate-use protocol has also proved useful. Clinical benefit associated with INPX treatment has been demonstrated in other patients with a depressed immune response, such as aged patients, cancer patients, severely burned patients, ill patients, and surgery patients. This program of clinical trials supports the therapeutic use of INPX in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.


Effects of Vimentin Intermediate Filaments on the Structure and Dynamics of In Vitro Multicomponent Interpenetrating Cytoskeletal Networks.
We investigate the rheological properties of interpenetrating networks reconstituted from the main cytoskeletal components: filamentous actin, microtubules, and vimentin intermediate filaments. The elastic modulus is determined largely by actin, with little contribution from either microtubules or vimentin. However, vimentin dramatically impacts the relaxation, with even small amounts significantly increasing the relaxation time of the interpenetrating network. This highly unusual decoupling between dissipation and elasticity may reflect weak attractive interactions between vimentin and actin networks.


Shotgun sequence-based metataxonomic and predictive functional profiles of Pe poke, a naturally fermented soybean food of Myanmar.
Pe poke is a naturally fermented sticky soybean food of Myanmar. The present study was aimed to profile the whole microbial community structure and their predictive gene functionality of pe poke samples prepared in different fermentation periods viz. 3 day (3ds), 4 days (4ds), 5 days (5ds) and sun-dried sample (Sds). The pH of samples was 7.6 to 8.7, microbial load was 2.1-3.9 x 108 cfu/g with dynamic viscosity of 4.0±1.0 to 8.0±1.0cP. Metataxonomic profile of pe poke samples showed different domains viz. bacteria (99.08%), viruses (0.65%), eukaryota (0.08%), archaea (0.03%) and unclassified sequences (0.16%). Firmicutes (63.78%) was the most abundant phylum followed by Proteobacteria (29.54%) and Bacteroidetes (5.44%). Bacillus thermoamylovorans was significantly abundant in 3ds and 4ds (p<0.05); Ignatzschineria larvae was significantly abundant in 5ds (p<0.05), whereas, Bacillus subtilis was significantly abundant in Sds (p <0.05). A total of 172 species of Bacillus was detected. In minor abundance, the existence of bacteriophages, archaea, and eukaryotes were also detected. Alpha diversity analysis showed the highest Simpson's diversity index in Sds comparable to other samples. Similarly, a non-parametric Shannon's diversity index was also highest in Sds. Good's coverage of 0.99 was observed in all samples. Beta diversity analysis using PCoA showed no significant clustering. Several species were shared between samples and many species were unique to each sample. In KEGG database, a total number of 33 super-pathways and 173 metabolic sub-pathways were annotated from the metagenomic Open Reading Frames. Predictive functional features of pe poke metagenome revealed the genes for the synthesis and metabolism of wide range of bioactive compounds including various essential amino acids, different vitamins, and enzymes. Spearman's correlation was inferred between the abundant species and functional features.


Monoclonal antibodies to human estrogen receptor.
Extranuclear estrogen receptor protein (estrophilin) of MCF-7 human breast cancer cells was purified by passage of the cytosol fraction of a cell homogenate through an affinity column of estradiol linked to Sepharose by a substituted di-n-propyl sulfide bridge in the 17 alpha position. Elution with 50 micro M [3H]estradiol in 10% (vol/vol) dimethyl formamide/0.5 M sodium thiocyanate gave 40% recovery of [3H]estradiol-estrophilin showing 14% of the specific radioactivity expected for the pure complex. Serum from a Lewis rat immunized with this partially purified estradiol-receptor complex contained antiestrophilin antibodies that reacted not only with nuclear and extranuclear estradiol-receptor complexes from MCF-7 cells but also with estrophilin from rat, calf, and monkey uterus, hen oviduct, and human breast cancers. Splenic lymphocytes from the immunized rat were fused with cells of two different mouse myeloma lines (P3-X63-Ag8 and Sp2/0-Ag14) to yield hybridoma cultures, 2% of which produced antibodies to estrophilin. After cloning by limiting dilution, three hybridoma lines secreting antiestrophilin were expanded in suspension culture and as ascites tumors in athymic mice to provide substantial quantities of monoclonal antibodies that recognize mammalian but not avian estrophilin and that show different degrees of reactivity with receptor from nonprimate sources. By growing the clone from Sp2/0 in the presence of [35S]methionine, radiolabeled monoclonal IgG has been prepared. These monoclonal antibodies should prove useful in the study of estrogen receptors of human reproductive tissues, in particular for the radioimmunochemical assay and immunocytochemical localization of receptors in breast cancers.


VACCINATION IN THE SYSTEM OF HUMAN RIGHTS AND OBLIGATIONS: IMPACT OF THE COVID-19 PANDEMIC.
The aim: To identify the problems and prospects of introducing mandatory vaccination against COVID-19 in the context of respect for human and civil rights and freedoms based on generalization and systematization of foreign experience in implementing such measures. Materials and methods: In the research, we applied a complex of philosophical and ideological approaches, general scientific and special methods of scientific cognition, in particular civilizational and axiological approaches as well as dialectical, dogmatic, comparative, and statistical methods. The empirical basis of the study is represented by the statistical data of the healthcare sector of European countries, generalization of the practice of vaccination. In the study, we use international and European regulatory legal acts and documents in the field of human rights, national legislation of foreign countries. Conclusions: Vaccination represents an important component of the fundamental right to health. International legal acts on the human rights regulation, in particular the right to health, do not provide an unambiguous answer to the question of whether vaccination is the right or responsibility of a person, which has resulted in the existence of a wide range of vaccination policies and models. The existence of a wide range of policies and practices in States Parties to the Convention makes permissible the application of more imperative approaches to immunization, in particular, in cases where voluntary vaccination is not sufficient to ensure the threshold of herd immunity. In most countries, vaccination against COVID-19 is carried out voluntarily, whereas the complication of the epidemiological situation has resulted in following the path of introducing mandatory vaccination in some countries, both with regard to certain population categories (France, Greece, Russia, Ukraine) and the entire population (Tajikistan, Turkmenistan).


A hidden Ising model for ChIP-chip data analysis.
Chromatin immunoprecipitation (ChIP) coupled with tiling microarray (chip) experiments have been used in a wide range of biological studies such as identification of transcription factor binding sites and investigation of DNA methylation and histone modification. Hidden Markov models are widely used to model the spatial dependency of ChIP-chip data. However, parameter estimation for these models is typically either heuristic or suboptimal, leading to inconsistencies in their applications. To overcome this limitation and to develop an efficient software, we propose a hidden ferromagnetic Ising model for ChIP-chip data analysis. We have developed a simple, but powerful Bayesian hierarchical model for ChIP-chip data via a hidden Ising model. Metropolis within Gibbs sampling algorithm is used to simulate from the posterior distribution of the model parameters. The proposed model naturally incorporates the spatial dependency of the data, and can be used to analyze data with various genomic resolutions and sample sizes. We illustrate the method using three publicly available datasets and various simulated datasets, and compare it with three closely related methods, namely TileMap HMM, tileHMM and BAC. We find that our method performs as well as TileMap HMM and BAC for the high-resolution data from Affymetrix platform, but significantly outperforms the other three methods for the low-resolution data from Agilent platform. Compared with the BAC method which also involves MCMC simulations, our method is computationally much more efficient. A software called iChip is freely available at http://www.bioconductor.org/. email@example.com.


Method validation for measurement of hair nicotine level in nonsmokers.
The development of strategies to address the growing worldwide burden of exposure to secondhand smoke (SHS) would be facilitated by sensitive and accurate methods for assessing SHS exposure. Hair provides a readily available matrix for assessing biomarkers of typical SHS exposure. We developed and applied an optimized analytical method using an isotope dilution gas chromatography-mass spectrometry (GC/MS) for hair nicotine measurement. The utility of this optimized method is illustrated by presenting data on SHS exposure of women and children from 31 countries. Using this isotope dilution method with spiked samples (3.3 ng/mg), we found that the greatest hair nicotine extraction efficiency was obtained with a 60 min shaking time. In the field study (n = 2400), a positive association was evident between hair nicotine concentrations from nonsmokers and higher numbers of cigarettes smoked per day in a household.


Role of free fatty acid receptors in the regulation of energy metabolism.
Free fatty acids (FFAs) are energy-generating nutrients that act as signaling molecules in various cellular processes. Several orphan G protein-coupled receptors (GPCRs) that act as FFA receptors (FFARs) have been identified and play important physiological roles in various diseases. FFA ligands are obtained from food sources and metabolites produced during digestion and lipase degradation of triglyceride stores. FFARs can be grouped according to ligand profiles, depending on the length of carbon chains of the FFAs. Medium- and long-chain FFAs activate FFA1/GPR40 and FFA4/GPR120. Short-chain FFAs activate FFA2/GPR43 and FFA3/GPR41. However, only medium-chain FFAs, and not long-chain FFAs, activate GPR84 receptor. A number of pharmacological and physiological studies have shown that these receptors are expressed in various tissues and are primarily involved in energy metabolism. Because an impairment of these processes is a part of the pathology of obesity and type 2 diabetes, FFARs are considered as key therapeutic targets. Here, we reviewed recently published studies on the physiological functions of these receptors, primarily focusing on energy homeostasis.


Open fractures of the tibia in HIV positive patients: a prospective controlled single-blind study.
Twenty-seven patients with severe open fractures were studied prospectively analysing infection and union as outcome measures. A standard treatment regime was applied. Seven patients were HIV positive, and 20 patients HIV negative. Wound infection and delayed union were more common in HIV positive patients. The difference in rate of infection was statistically significant (P = 0.020), while that in union did not quite reach significance (P = 0.059). The authors have developed an algorithm for treatment of these injuries in areas of high seroprevalence of HIV infection.


Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division.
Polo-like kinases (Plks) are key cell cycle regulators. They contain a kinase domain followed by a polo-box domain that recognizes phosphorylated substrates and enhances their phosphorylation. The regulatory subunit of the Dbf4-dependent kinase complex interacts with the polo-box domain of Cdc5 (the sole Plk in Saccharomyces cerevisiae) in a phosphorylation-independent manner. We have solved the crystal structures of the polo-box domain of Cdc5 on its own and in the presence of peptides derived from Dbf4 and a canonical phosphorylated substrate. The structure bound to the Dbf4-peptide reveals an additional density on the surface opposite to the phospho-peptide binding site that allowed us to propose a model for the interaction. We found that the two peptides can bind simultaneously and non-competitively to the polo-box domain in solution. Furthermore, point mutations on the surface opposite to the phosphopeptide binding site of the polo-box domain disrupt the interaction with the Dbf4 peptide in solution and cause an early anaphase arrest phenotype distinct from the mitotic exit defect typically observed in cdc5 mutants. Collectively, our data illustrates the importance of non-canonical interactions mediated by the polo-box domain and provide key mechanistic insights into the combinatorial recognition of substrates by Polo-like kinases.


Interconversion of type C and D strains of Clostridium botulinum by specific bacteriophages.
These studies show that Clostridium botulinum types C and D cultures can be cured of their prophages and converted to either type C or D depending on the specific phage used. Strains of types C and D were cured of their prophages and simultaneously ceased to produce their dominant toxins designated as C(1) and D, respectively. Cured nontoxigenic cultures derived from type C strain 162 were sensitive to the phages from the toxigenic type C strain 162 and type D strain South African. When cured nontoxigenic cultures derived from strain 162 were infected with the tox(+) phages from the 162 strain of type C and the South African strain of type D, they then produced toxin neutralized by types C and D antisera, respectively. Cured nontoxigenic cultures isolated from the type D South African strain were only sensitive to the parent phage, and, when reinfected with the tox(+) phage, they produced toxin neutralized by type D antiserum. Type C strain 153 and type D strain 1873, when cured of their respective prophages, also ceased to produce toxins C(1) and D, but, unlike strain 162 and the South African strain, they continued to produce a toxin designated as C(2). When the cured cultures from strains 153 and 1873 were infected with the tox(+) phage from type D strain 1873, the cultures simultaneously produced toxin that was neutralized by type D antiserum. When these cured cultures were infected with the tox(+) phage from type C strain 153, the cultures produced toxin that was neutralized by type C antiserum. These studies with the four strains of C. botulinum confirm that the toxigenicity of types C and D strains requires the continued participation of tox(+) phages. Evidence is presented that types C and D cultures may arise from a common nontoxigenic strain.


A Mobile Phone-Based App for Use During Cognitive Behavioral Therapy for Adolescents With Anxiety (MindClimb): User-Centered Design and Usability Study.
Mobile device-based tools to help adolescents practice skills outside of cognitive behavioral therapy (CBT) sessions for treating an anxiety disorder may lead to greater treatment gains. This study aimed to develop, design, and test the acceptability, learnability, heuristics, and usability of MindClimb, a smartphone-based app for adolescents with anxiety to use between CBT sessions to plan and complete exposure activities using skills (cognitive, relaxation, exposure practice, and reward) learned in treatment. This 3-phase study took place from August 2015 to December 2018. In phase 1, the app was designed and developed in consultation with young people and CBT therapists to identify desired functions and content. Feedback was subjected to thematic analysis using a general inductive approach. In phase 2, we conducted 2 high-fidelity testing sessions using the think-aloud approach (acceptability, learnability, usability) and 10-item System Usability Scale with 10 adolescents receiving CBT. The high-fidelity MindClimb app was evaluated by 5 app developers based on Nielsen's usability heuristics and 5-point severity ranking scale. In phase 3, a total of 8 adolescents and 3 therapists assessed the usability of MindClimb during CBT sessions by recording the frequency of skills practice, use of MindClimb features, satisfaction with the app, and barriers and facilitators to app use during treatment. Feedback from phase 1 consultations indicated that the app should (1) be responsive to user needs and preferences, (2) be easy to use and navigate, (3) have relevant content to the practice of CBT for anxiety, and (4) be aesthetically appealing. Using this feedback as a guide, a fully functional app prototype for usability testing and heuristic evaluation was developed. In phase 2, think-aloud and usability data resulted in minor revisions to the app, including refinement of exposure activities. The average system usability score was 77 in both testing cycles, indicating acceptable usability. The heuristic evaluation by app developers identified only minor errors (eg, loading speed of app content, with a score of 1 on the severity ranking scale). In phase 3, adolescents considered app features for completing exposure (6.2/10) and relaxation (6.4/10) modestly helpful. Both adolescents (average score 11.3/15, SD 1.6) and therapists (average score 10.0/12, 2.6 SD) reported being satisfied with the app. The user-centered approach to developing and testing MindClimb resulted in a mobile health app that can be used by adolescents during CBT for anxiety. Evaluation of the use of this app in a clinical practice setting demonstrated that adolescents and therapists generally felt it was helpful for CBT practice outside of therapy sessions. Implementation studies with larger youth samples are necessary to evaluate how to optimize the use of technology in clinical care and examine the impact of the app plus CBT on clinical care processes and patient outcomes.


Association Between Epidural Analgesia and Cancer Recurrence or Survival After Surgery for Renal Cell Carcinoma: A Propensity Weighted Analysis.
Whether epidural anesthesia and analgesia (EA) is beneficial for postoperative cancer outcomes remains controversial and we conducted this historical cohort study to evaluate the association between EA and long-term outcomes following surgery for renal cell carcinoma (RCC). We collected patients receiving RCC surgery from 2011 to 2017 and followed up them until February 2020. Patient attributes, surgical factors and pathological features were gathered through electronic medical chart review. The association between EA and recurrence-free and overall survival after surgery was evaluated using Cox regression models with inverse probability of treatment weighting (IPTW) to balance the observed covariates. The median follow-up time for the 725 included patients was 50 months (interquartile range: 25.3-66.5) and 145 of them (20%) received perioperative EA. We demonstrated EA use was associated with better recurrence-free survival [IPTW adjusted hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.49-0.83, p < 0.001] and overall survival [IPTW adjusted HR: 0.66, 95% CI: 0.49-0.89, p = 0.006] in patients receiving surgical resection for RCC. More prospective studies are needed to verify this connection between EA and superior cancer outcomes after RCC surgery.


Antioxidant and Biological Activities of Proteinaceous Extract from Algerian Glycine max Plant.
Glycine max is commonly used in Algeria for treatment of anemia deficiency and osteoporosis, it ranks first in terms of vegetal proteins. The experiment was aimed at characterizing the proteinaceous Glycine max extract and evaluating its antioxidant, biological and hematological potential. Extraction of proteinaceous materials from Glycine max plant was undertaken using water and n-hexane as extracting media. The isolation of proteins from the crude materials was done, providing the use of ammonium sulfate. The Glycine max proteins were characterized by UV-visible and FT-IR spectroscopy and analyzed by SEM micrograph and x-ray diffraction (XRD). Rheological parameters G' and G'' were assessed. The isolated proteins were tested for their antioxidant, antimicrobial and hemagglutination activities. There was a gelling effect of the protein extract which can be used as an alternative in principally made vaccines with its microbiological and antifungal activities. The proteinaceous extract from Algerian Glycine max would have a potential use in biomedical application.


An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation.
Methylated histones H3K9 and H3K27 are canonical epigenetic silencing modifications in metazoan organisms, but the relationship between the two modifications has not been well characterized. H3K9me3 coexists with H3K27me3 in pluripotent and differentiated cells. However, we find that the functioning of H3K9me3 is altered by H3S10 phosphorylation in differentiated postmitotic osteoblasts and cycling B cells. Deposition of H3K9me3/S10ph at silent genes is partially mediated by the mitogen- and stress-activated kinases (MSK1/2) and the Aurora B kinase. Acquisition of H3K9me3/S10ph during differentiation correlates with loss of paused S5 phosphorylated RNA polymerase II, which is present on Polycomb-regulated genes in embryonic stem cells. Reduction of the levels of H3K9me3/S10ph by kinase inhibition results in increased binding of RNAPIIS5ph and the H3K27 methyltransferase Ezh1 at silent promoters. Our results provide evidence of a novel developmentally regulated methyl-phospho switch that modulates Polycomb regulation in differentiated cells and stabilizes repressed states.


Evaluating methods of correcting for multiple comparisons implemented in SPM12 in social neuroscience fMRI studies: an example from moral psychology.
In fMRI research, the goal of correcting for multiple comparisons is to identify areas of activity that reflect true effects, and thus would be expected to replicate in future studies. Finding an appropriate balance between trying to minimize false positives (Type I error) while not being too stringent and omitting true effects (Type II error) can be challenging. Furthermore, the advantages and disadvantages of these types of errors may differ for different areas of study. In many areas of social neuroscience that involve complex processes and considerable individual differences, such as the study of moral judgment, effects are typically smaller and statistical power weaker, leading to the suggestion that less stringent corrections that allow for more sensitivity may be beneficial and also result in more false positives. Using moral judgment fMRI data, we evaluated four commonly used methods for multiple comparison correction implemented in Statistical Parametric Mapping 12 by examining which method produced the most precise overlap with results from a meta-analysis of relevant studies and with results from nonparametric permutation analyses. We found that voxelwise thresholding with familywise error correction based on Random Field Theory provides a more precise overlap (i.e., without omitting too few regions or encompassing too many additional regions) than either clusterwise thresholding, Bonferroni correction, or false discovery rate correction methods.


Continuing education for health professionals.
Although continuing education in the health professions is an important endeavor, it has been largely neglected in the professional literature. Few studies have been done on (a) conceptual models to guide the design and implementation of continuing education and (b) the use of such models in continuing education. To fill this gap, two such models are described in this article: (a) instructional development and (b) community development. Combining and using these models can lead to more effective continuing education with more enduring effects. Principles to guide the implementation of these models are presented. An arthritis continuing education project based on the instructional and community development models is used to illustrate these principles. This continuing education project focused on occupational and physical therapists in clinical practice.


Fatigue associated with stroke and other neurologic conditions: Implications for stroke rehabilitation.
To examine the general phenomenon of fatigue in stroke and other neurologic disorders and to review what is currently known about its occurrence, including its frequency, duration, severity, and associated factors, to develop a strategy for treatment. Computerized databases (eg, PubMed, PsycInfo, Science Citation Index, Ovid EMBASE, Ovid MEDLINE) searched from inception to May 2002. Additional references were identified from bibliographies of pertinent articles and books. Over 1000 articles were identified as relevant to fatigue experienced by patients with neurologic or nonneurologic disorders. Articles on fatigue in stroke and neurologic disorders, mechanisms, and/or treatment were selected for inclusion. Authors reviewed the articles and assessed the purpose, study design, and conclusions for validity and relevance to the topic of fatigue in stroke. Fatigue is a common complaint among patients with neurologic disorders including stroke. Few studies have documented the high frequency of fatigue in poststroke patients and its negative impact on daily functioning and quality of life. Little is known about associated factors or about therapeutic strategies that may be used to alleviate it. Examination of fatigue in other neurologic populations suggests common characteristics and associated factors that may be useful in the development of potential therapeutic strategies. Pharmacologic and nonpharmacologic therapeutic interventions, such as stimulants, amantadine, or sleep and stress-management education, have been used with some success in neurologic and other patient populations (eg, multiple sclerosis, human immunodeficiency virus, acquired immune deficiency syndrome, cancer), but evidence of effectiveness based on randomized clinical trials is rare. Poststroke fatigue is common. Therapeutic strategies have been used to treat fatigue in other patient populations, but it is unclear whether these will be beneficial to poststroke patients. Frequency, severity, duration, impact, predisposing factors, and causes of poststroke fatigue, as well as the development of effective treatment, require further research. Criteria for assessment of fatigue and potential therapeutic interventions are outlined as a first step for stimulating further research.


Endocrine causes of amenorrhea.
Amenorrhea is a symptom of a variety of disorders and dysfunctions. It is important for the primary care practitioner to have an understanding of what constitutes normal function and of when to begin a diagnostic assessment of women with amenorrhea. Definitions and the basic principles of menstrual function are reviewed. Causes of amenorrhea are presented, including disorders of the uterus, disorders of the ovary, disorders of the anterior pituitary, and disorders of the central nervous system. The hypothalamic-pituitary-ovarian-uterine axis is used as a framework for the differential diagnosis of amenorrhea. A detailed process for assessing patients with amenorrhea is offered. Components of a amenorrheic-specific history, including menstrual, sexual and contraceptive, life-style, family, and medical histories, are reviewed. A step-by-step laboratory assessment is presented. Management of amenorrhea and health promotion strategies are discussed. The role of primary practitioners caring for amenorrheic women is outlined.


Contract litigation: prepare for war to ensure peace.
Contract litigation can prove devastating for all but the deepest of pockets. Physicians need to prepare for war to ensure the most favorable outcome. This includes identifying your risks, negotiating from strength, and hedging your bets. Negotiate and read your contracts carefully. Beware of critical loser pays provisions in your contracts that will require you to pay your adversary's fees in the event of an adverse ruling at trial or summary judgment. Keep your insurance portfolio up to date, including the latest risk management tools, such as contract litigation insurance. Protect yourself and your practice by planning ahead.


Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts.
Absorption of urea in the renal inner medullary collecting duct (IMCD) contributes to hypertonicity in the medullary interstitium which, in turn, provides the osmotic driving force for water reabsorption. This mechanism is regulated by vasopressin via a cAMP-dependent pathway and activation of a specialized urea transporter located in the apical membrane. We report here the cloning of a novel urea transporter, designated UT1, from the rat inner medulla which is functionally and structurally distinct from the previously reported kidney urea transporter UT2. UT1 expressed in Xenopus oocytes mediated passive transport of urea that was inhibited by phloretin and urea analogs but, in contrast to UT2, was strongly stimulated by cAMP agonists. Sequence comparison revealed that the coding region of UT1 cDNA contains the entire 397 amino acid residue coding region of UT2 and an additional 1,596 basepair-stretch at the 5' end. This stretch encodes a novel 532 amino acid residue NH2-terminal domain that has 67% sequence identity with UT2. Thus, UT1 consists of two internally homologous portions that have most likely arisen by gene duplication. Studies of the rat genomic DNA further indicated that UT1 and UT2 are derived from a single gene by alternative splicing. Based on Northern analysis and in situ hybridization, UT1 is expressed exclusively in the IMCD, particularly in its terminal portion. Taken together, our data show that UT1 corresponds to the previously characterized vasopressin-regulated urea transporter in the apical membrane of the terminal IMCD which plays a critical role in renal water conservation.


The redox state of glutathione, cysteine and homocysteine in the extracellular fluid in the skin.
Glutathione, the most abundant low-molecular weight thiol in the skin, has been shown to protect the skin from both photobiological and chemical injury. The thiols, glutathione in particular, have also been shown to be crucially involved in defence against contact allergens. Since the levels of extracellular thiol concentrations are important determinants of intracellular thiol status, we have compared the normal concentrations and the redox status of the main low-molecular weight thiol components in the extracellular fluid at the dermo-epidermal junction with the corresponding plasma levels. In their sulfhydryl form, all three thiols, i.e. glutathione, cysteine and homocysteine, were more abundant in experimental skin blister fluid than in plasma, as were the free disulfides of glutathione and homocysteine, whereas the free disulfides of cysteine were about the same in blister fluid and in plasma. Protein mixed disulfide levels were higher in plasma than in blister fluid. The present results provide information concerning the extracellular defence in the skin.


Copy number control of Tn5 transposition.
Transposition of Tn5 in Escherichia coli strains containing one or multiple copies of the transposable element was investigated. It was found that the overall frequency of transposition within a cell remained constant regardless of the number of copies of Tn5 present in that cell. Experiments measuring the transposition frequency of differentially marked Tn5s confirmed that the frequency of transposition of an individual Tn5 decreased proportionally with the total number of copies of the element present in a cell. The IS50R -encoded function, protein 2, which has previously been shown to be an inhibitor of transposition, is sufficient to mediate this inhibitory effect. The concentration of protein 2 in a cell appears to modulate the transposition of individual Tn5 elements in such a way that the overall transposition of Tn5 in a cell remains constant.


Double-paddle peroneal tissue transfer for oromandibular reconstruction.
The double-paddle peroneal tissue transfer is a useful technique for reconstructing the extensive and complex defect that results after ablative surgery for oral cancer. It can facilitate the design and inset of the skin paddle and avoid the need for a second free flap. The two skin paddles can be based on either two cutaneous perforators of the peroneal vessels or two branches of a single cutaneous perforator. The authors report their experience with double-paddle peroneal tissue flaps (10 fasciocutaneous and five osteocutaneous) in 15 patients. The largest double paddle used was (16 x 9) (15 x 6) cm, and the smallest one was (7 x 5.5) (4.5 x 4) cm. All flaps were used for both intraoral and extraoral defect reconstruction. There was one single skin paddle necrosis caused by erroneous manipulation of the flap 1 week after the operation; however, the skin paddle had survived completely before the manipulation. All other flaps survived completely, with a good to excellent appearance, and no patient had a significant gait disturbance after the operation.


Factors associated with recent increase of multiple births in Spain.
The increased incidence of multiple deliveries in Spain, in addition to changes in age at maternity and parity, is attributed to assisted reproductive treatments, but the relative contribution of the latter to this rise remains uncertain, due to the scarce information provided by clinics practicing those treatments. Population based data (1984-2004), including information on mother's age, nationality, marital status, date of delivery, and the characteristics of each (parity, single or multiple), and sex of newborns were provided by the Spanish Institute of Statistics. Twinning and triplet deliveries relate to maternal age, parity, and nationality. For younger ages (<or= 19, 20-24, 25-29) rates remained constant over time, but for older women (30-34, 35-39, >or= 40) rates increased after 1994. From 1984 to 2004 the percentage of twins of opposite sex increased from 24.31 to 36.58 per cent. Since 1997, Spanish and non-Spanish mothers differentiate with respect to multiple maternity at ages over 30. In addition to unmarried Spanish women, immigrants constitute a reliable reference group that determines the convenience of segregating information on multiple deliveries respecting origin. The proportion of twins and triplets of opposite sex, maternal age, and parity patterns observed are concordant with a differential access to reproductive treatments depending on the woman's age. The present norm regulating the maximum number of fertilizations per cycle and the demand for these treatments explain the high incidence of multiple deliveries in Spain. A modified logistic curve predicts a stabilization of multiple deliveries, which will probably continue to be high in Spain.


Cross lid flap for repair of large upper eyelid defects.
A 2-stage technique for reconstruction of large, upper eyelid defects was adapted from a technique used in man for use in lower animals. The technique utilized a flap from the lower lid and was applied successfully in a dog with a melanoma and in 2 cats with colobomas.


[Prevalence of antibodies to Borrelia burgdorferi in Sardinian teen-agers].
A cross-sectional sero-epidemiological study was conducted on teen-agers in Northern Sardinia, a low risk population for Lyme borreliosis. The adjusted sero-prevalence estimate for Enzyme Linked Immunofluorescent Assay on 443 teen-agers (229 males and 214 females) was 6.1%. The females vs males Odds Ratio was 5.1 (CI95%: 2.1-12.8). The prevalence was associated with the family size (chi2 for trend: p=0.03); teenagers without cohabitants, except parents, had a five fold risk (CI95%: 1.2-20.7) of sero-positivity in comparison to those with wider families. No significant association was found with other socio-economical indices nor with pet-owning. In conclusion, positive Lyme serology is not common in Northern Sardinia, but further sero-epidemiological survey on at high-risk population (forestry workers, hunters, shepherds) are needed.


What do physicians want in their ideal job?
This article explores the question of what physicians want in their "ideal job" using a nationally representative sample of physicians in ambulatory practice. The importance of ten work values was examined overall by specialty, practice setting, race/ethnicity, age, and gender. More than 90% of physicians rated the following as very important: good relationships with staff and colleagues; control of time off; adequate material resources; and autonomy in decision making. Remarkably, the relative importance of these work values remained consistent across each grouping. As more physicians practice in organized settings, there is a greater potential for a clash of work values to occur between physicians and their practice organizations. The consequences for physicians include lower job satisfaction and a greater likelihood of quitting. Practice organizations suffer through lower patient satisfaction and increased recruiting costs. Based on our findings, we offer five recommendations to maximize the well-being of physicians in ambulatory care settings.


Scientific writing: strategies and tools for students and advisors.
Scientific writing is a demanding task and many students need more time than expected to finish their research articles. To speed up the process, we highlight some tools, strategies as well as writing guides. We recommend starting early in the research process with writing and to prepare research articles, not after but in parallel to the lab or field work. We suggest considering scientific writing as a team enterprise, which needs proper organization and regular feedback. In addition, it is helpful to select potential target journals early and to consider not only scope and reputation, but also decision times and rejection rates. Before submission, instructions to authors and writing guides should be considered, and drafts should be extensively revised. Later in the process editor's and reviewer's comments should be followed. Our tips and tools help students and advisors to structure the writing and publishing process, thereby stimulating them to develop their own strategies to success.


Predicting inpatient clinical order patterns with probabilistic topic models vs conventional order sets.
Build probabilistic topic model representations of hospital admissions processes and compare the ability of such models to predict clinical order patterns as compared to preconstructed order sets. The authors evaluated the first 24 hours of structured electronic health record data for > 10 K inpatients. Drawing an analogy between structured items (e.g., clinical orders) to words in a text document, the authors performed latent Dirichlet allocation probabilistic topic modeling. These topic models use initial clinical information to predict clinical orders for a separate validation set of > 4 K patients. The authors evaluated these topic model-based predictions vs existing human-authored order sets by area under the receiver operating characteristic curve, precision, and recall for subsequent clinical orders. Existing order sets predict clinical orders used within 24 hours with area under the receiver operating characteristic curve 0.81, precision 16%, and recall 35%. This can be improved to 0.90, 24%, and 47% ( P < 10 -20 ) by using probabilistic topic models to summarize clinical data into up to 32 topics. Many of these latent topics yield natural clinical interpretations (e.g., "critical care," "pneumonia," "neurologic evaluation"). Existing order sets tend to provide nonspecific, process-oriented aid, with usability limitations impairing more precise, patient-focused support. Algorithmic summarization has the potential to breach this usability barrier by automatically inferring patient context, but with potential tradeoffs in interpretability. Probabilistic topic modeling provides an automated approach to detect thematic trends in patient care and generate decision support content. A potential use case finds related clinical orders for decision support.


Feeling the power: robust supercapacitors from nanostructured conductive polymers fostered with Mn2+ and carbon dots.
Polyaniline (PANI) is considered one of the most preferred electrically conductive polymers (CPs), which is widely studied as an electrode material in designing next-generation energy storage devices due to their chemical stability, fast redox reactions between the polymer and the electrolytes, high electrical conductivity, excellent electrochemical performance, and low cost. However, the inferior stability of PANI limits its application. In this work, the benefit of carbon dots (CDots) as light-weight and spherical carbon-based electrodes and fillers that allow the maintenance of the nanostructure of PANI while easing the ionic transport was studied together with the effect of manganese(ii) (Mn2+) doping on the overall capacitive properties of PANI. The integration of N-doped spherical, nanosized carbon dots (N-CDots) in the copolymerization of nanostructured PANI in the presence of varying concentrations of Mn2+ as a dopant synergistically improved the overall conductivity and specific surface area of the PANI-based electrode and showed surface double layer ion exchange. Pseudocapacitance mechanisms were observed when the dopant concentration was kept at a molar percentage of Mn2+ to aniline of 1, which displayed exceptionally high specific capacitances of up to 595 F g-1. The asymmetric supercapacitor devices made with N-CDot and nanostructured hybrid electrodes could reveal the great potential in the development of cheap yet efficient battery-sized supercapacitor devices. In addition to extensive electrochemical performance, advanced EPR spectroscopy revealed detailed information regarding the defect structures of electrode materials in terms of understanding the conduction behavior of defect centers.


[Acupuncture in the treatment of gastroenteric diseases in children].
Individual regimens of acupuncture were applied in treatment of 66 children with various gastrointestinal diseases. As a result, the effect of the combined treatment rose 1.4-fold.


Reasons to Amplify the Role of Parental Permission in Pediatric Treatment.
Two new documents from the Committee on Bioethics of the American Academy of Pediatrics (AAP) expand the terrain for parental decision making, suggesting that pediatricians may override only those parental requests that cross a harm threshold. These new documents introduce a broader set of considerations in favor of parental authority in pediatric care than previous AAP documents have embraced. While we find this to be a positive move, we argue that the 2016 AAP positions actually understate the importance of informed and voluntary parental involvement in pediatric decision making. This article provides a more expansive account of the value of parental permission. In particular, we suggest that an expansive role for parental permission may (1) reveal facts and values relevant to their child's treatment, (2) encourage resistance to suboptimal default practices, (3) improve adherence to treatment, (4) nurture children's autonomy, and (5) promote the interests of other family members.


FFR guided PCI on long coronary lesions: 2-year clinical results with 2nd or newer generation DES.
Background. Despite improvements in drug-eluting stent (DES) technology, treatment strategies for long coronary artery lesions remain a controversial issue. The aim of our study was to evaluate the long-term clinical results after FFR guided PCI on long coronary lesions. Materials and methods. A total of 74 consecutive patients with significant (mean FFR 0.61 ± 0.11) coronary artery lesions ≥30 mm in length were included in the prospective study. All patients were treated with FFR guided PCI implanting newer generation Biolimus, Everolimus or Zotarolimus eluting stents. Clinical endpoints - target vessel revascularization (TVR) and major adverse cardiac events (MACE) - were recorded at 1 and 2 years. Results. 100% angiographic procedure success was achieved, the mean post procedural FFR was 0.88 ± 0.06. At 2-year follow-up, 6 (8.1%) patients had ischemia driven TVR, all within the first 12 months. There were no target vessel related acute coronary syndromes and definite stent thromboses in the study group. At 2 years, the total MACE rate was 29.7%. There was a trend towards a higher TVR rate in patients with overlapping DES vs single DES implanted (9.6 vs 4.5%, p = 0.6). On regression analysis, the total stent length had no influence on the TVR rate. Conclusions. At 2 years after stenting long coronary lesions with newer generation DES the TVR rate was 8.1%, which is acceptable in the high cardiovascular risk population with diffuse coronary artery disease. The total stent length did not affect the long-term clinical outcomes.


Endoscopic laser therapy for malignancies affecting the esophagus and gastroesophageal junction. Analysis of technical and functional efficacy.
Thirty consecutive patients with far-advanced cancer affecting the esophagus and gastroesophageal junction underwent palliative endoscopic neodymium-YAG laser therapy. No patients were excluded from treatment, regardless of age, extent of disease, or performance status. Sessions were performed every other day and concluded when an endoscope could be easily passed beyond the previously obstructed area. Treatment was completed in 3.3 sessions (seven days). Luminal patency was achieved in 97%, but did not always equate with functional success. Seventy percent (21 patients) were able to ingest all necessary calories and leave hospital for home (functional success). Reasons for discrepancy between technical success and functional success included radiation-induced pharyngeal dysphagia, anorexia, painful tumor load and debility, and treatment complications. Endoscopic laser therapy of far-advanced esophageal or gastroesophageal junction carcinoma was almost always technically feasible, with relatively low morbidity. While technical success could not always be equated with functional success, therapy was "completely" functionally successful in 70% of patients with far-advanced disease. Poor performance status at accession correlated best with poor functional outcome.


Strategic re-design of team-based patient-focused health care services.
This paper proposes an organizational change process to prepare physicians and other health professionals for their new roles in patient-centered medical homes (PCMHs). It provides physician-centered tools, models, concepts, and the language to implement transformational patient-centered medical care. To improve care delivery, quality, and patient engagement, a systems approach to care is required. This paper examines a systems approach to patient care where all inputs that influence patient interactions and participation are considered in the design of health care delivery and follow-up treatment plans. Applying systems thinking, organizational change models, and team-building, we have examined the continuum of this change process from ideation through the diffusion of new methods and behaviors. PCMHs make compelling business sense. Studies have shown that the PCMH improves patient satisfaction, clinical outcomes and reduces underuse and overuse of medical services. Patient-centered care necessitates transitioning from an adversarial to a collaborative culture. It is a transformation process predicated on strong leadership able to align an organization toward a vision of patient-centered care, creating a collaborative culture committed to health-goal achievement. This paper proposes that the PCMH is a rigorous team-building transformational organizational change, a radical departure from the current hierarchical, silo-oriented, medical practice model. It requires that participants within and across health care organizations learn new skills and behaviors to achieve the anticipated quality and efficiency improvements. It is an innovative health care organization model of the future whose success is premised on teams supplanting the individual as the building block and unit of health care performance.


Finding the cure for primary biliary cholangitis - Still waiting.
The introduction of ursodeoxycholic acid (UDCA)may well have contributed to some of the improvements in morbidity and mortality of primary biliary cholangitis (PBC). Yet nearly 40% of PBC patients are unresponsive to UDCA. Further the data on UDCA is confounded by the changes in the goepidemiology and particularly the earlier diagnosis of PBC. In this regard we welcome the addition of obeticholic acid (OCA) as an alternative therapeutic option forthe treatment of PBC in those patients refractory to UDCA. However, OCA is intellectually disappointing.There is no data on OCA that reflects dynamic and critical endpoints, for example death or liver transplantation; only surrogate endpoints have been used in the clinical trials. A nested study with liver histology wouldbeanideal surrogate marker,including intensive use of immunohistochemistry to define cellular infiltrates and cytokine/chemokine activity. More importantly, the clinical characteristics of PBCmay vary among patients and progression is not always predictable. We need to identify more appropriate and specific biomarkers that predict the clinical course, and we need to know which therapies are applicable at different stages, since treatmentfor PBC should be individualized. We need to know more about the etiology of PBC,and we want a cure for PBC.


Economic Evaluations of First-Line Chemotherapy Regimens for Pancreatic Cancer: A Critical Review.
Effect sizes of efficacy of first-line treatments for (metastatic) pancreas cancer are constrained, underscoring the need for evaluations of the efficacy-to-cost relationship. We critically review economic evaluations of first-line chemotherapy regimens for pancreatic cancer since the 1997 introduction of gemcitabine. We searched PubMed/MEDLINE and EMBASE (1997-2015), and the websites of health technology assessment agencies. Two authors independently reviewed economic studies for eligibility in this review; evaluated peer-reviewed, journal-published studies in terms of the Drummond Checklist; and critiqued the technical and scientific merit of all studies. Sixteen pharmacoeconomic evaluations were included: ten published in nine peer-reviewed journals and six on three websites. Six were on single-agent therapies and ten on combination therapies. Analyses conducted included cost-effectiveness (three studies), cost-utility (one study), or combined cost-effectiveness and cost-utility (12 studies). Studies diverged in results, mainly because of different assumptions, methods, inputs, and country-specific guidelines. The two most recent regimens, nanoparticle albumin-bound paclitaxel plus gemcitabine (NAB-P + GEM) and the combination of fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX), were evaluated in an indirect comparison, yielding a statistically similar benefit in overall survival but superior progression-free survival for FOLFIRINOX. NAB-P + GEM showed greater economic benefit over FOLFIRINOX. In conclusion, the divergence in results observed across studies is attributable to economic drivers that are specific to countries and their healthcare (financing) systems. No recommendations regarding the relative economic benefit of treatment regimens, general or country-specific, are made as the purpose of pharmacoeconomic analysis is to inform policy decision-making and clinical practice, not set policy or define clinical practice.


Genetic contribution to high neonatally lethal malformation rate in the United Arab Emirates.
We examined the contribution of genetic disorders to congenital anomalies (CA) causing neonatal deaths in the Al Ain Medical District (AMD) in the United Arab Emirates (UAE) because of the high consanguineous marriage rate in the community. Charts of all neonatal deaths in the three perinatal units, which accounted for 99% of all births in AMD (1992-2000), were studied. Data regarding pregnancy, a family history including the level of parental consanguinity, the results of genetic evaluations and neonatal outcomes were recorded as part of an ongoing malformation surveillance system. Causes of death were based on clinical, laboratory and imaging findings. Of the 508 neonates who died, 212 (42%) had CA, which were the leading cause of death. Forty-four percent of the CA were due to definite genetic disorders and 75% of these were single gene defects. Multisystem malformations were the commonest congenital malformations. Parental consanguinity was associated with a 2-fold increased risk of non-chromosomal multisystem malformations. Lethal malformations were the leading cause of neonatal deaths, and parental consanguinity was associated with an increased risk of autosomal recessive disorders. The results underscore the importance of genetic screening and counseling in strategies for further significant reductions in the neonatal mortality rate in the UAE.


The competitive exclusion-tolerance rule explains habitat partitioning among co-occurring species of burying beetles.
Habitat partitioning among co-occurring, ecologically similar species is widespread in nature and thought to be an important mechanism for coexistence. The factors that cause habitat partitioning, however, are unknown for most species. We experimentally tested among three alternative hypotheses to explain habitat partitioning among two species of co-occurring burying beetle (Nicrophorus) that occupy forest (Nicrophorus orbicollis) and wetland (Nicrophorus hebes) habitats. Captive experiments revealed that the larger N. orbicollis (forest) was consistently dominant to N. hebes (wetland) in competitive interactions for carcasses that they require for reproduction. Transplant enclosure experiments in nature revealed that N. hebes had poor reproductive success whenever the dominant N. orbicollis was present. In the absence of N. orbicollis, N. hebes performed as well, or better, in forest versus its typical wetland habitat. In contrast, N. orbicollis performed poorly in wetlands regardless of the presence of N. hebes. These results support the competitive exclusion-tolerance rule where the competitively dominant N. orbicollis excludes the subordinate N. hebes from otherwise suitable or preferable forest habitat, while the subordinate N. hebes is uniquely able to tolerate the challenges of breeding in wetlands. Transplant experiments further showed that carcass burial depth-an important trait thought to enhance the competitive ability of the dominant N. orbicollis-is costly in wetland habitats. In the presence of N. hebes, N. orbicollis buried carcasses deeper; deeper burial is thought to provide a competitive advantage in forests but further compromised the reproductive success of N. orbicollis in wetlands. Overall, results provide evidence that the competitive exclusion-tolerance rule underlies habitat partitioning among ecologically similar species and that the traits important for competitive dominance in relatively benign environments are costly in more challenging environments, consistent with a trade-off.


Trainees' adenoma detection rate is higher if ≥ 10 minutes is spent on withdrawal during colonoscopy.
It has been demonstrated that prolonged colonoscopic withdrawal times (WT; >6 min) are beneficial for the adenoma detection rate (ADR) for experienced endoscopists. There are little data, however, to guide the appropriate colonoscopic withdrawal times for trainees. The purpose of this study was to determine whether there is a relationship between WTs and ADR for first-year fellows training in colonoscopy. This is a prospective study of first-year gastroenterology fellows at a single academic teaching hospital who documented each colonoscopy with a self-report form over the course of an academic year (March 2010 to February 2011). The internal policy for the trainees was to have at least a 6-min withdrawal time for each colonoscopy. Four first-year fellows in gastroenterology at an academic medical center completed self-reports for 1,210 colonoscopies. Mean WT was 10.2 ± 3.4 min. The aggregate polyp detection rate was 33.2% and the aggregate ADR was 22.3%. For colonoscopies with WT < 10 min, ADR was 9.5%, and for colonoscopies with WT ≥ 10 min, ADR was 32.3% (p < 0.001). When the quality indicator of 25% goal ADR for males and 15% goal ADR for females is applied, this aggregate rate is achieved for both sexes for screening colonoscopies (n = 676) with WT ≥ 10 min. First-year trainees had a significantly higher ADR if their colonoscopic WT is ≥ 10 min.


Disulfide Click Reaction for Stapling of S-terminal Peptides.
A disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17-membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S-terminal peptides from 3 to 18 amino acid residues to provide 18- to 48-membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti-HCT-116 activity with a locked α-helical conformation (IC50 =6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2-carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three-dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.


A Review of Diagnostic and Therapeutic Dacryoendoscopy.
To provide a systematic review of the literature on diagnostic and therapeutic indications, techniques, utility, and complications of dacryoendoscopy (DEN). The authors performed a PubMed search of articles published in English/German/Japanese/Chinese on DEN. Data captured include evolution and techniques, diagnostic utility, therapeutic interventions, outcomes, and limitations. Specific emphasis was laid on addressing the current practice patterns and existing lacunae. Diagnostic DEN has enabled the exact localization and differentiation of mucosal edema, stenosis, strictures, and obstructions throughout the lacrimal drainage system (LDS). Guided expansion of the stenosis, laser dacryoplasty (LDP) for strictures and microdrill removal of dacryoliths (microdrill dacryoplasty [MDP]) are some of the therapeutic uses of DEN. Successful outcomes of up to 60%-70% were achieved with stenosis anywhere along the LDS with a restenosis rate of 20%. Longer segment of stenosis (>2 mm), presence of enlarged lacrimal sac, history of dacryocystitis, postsaccal stenosis, and complete obstruction were associated with poorer outcomes. Microendoscopic procedures like LDP or MDP achieve canalicular and NLD recanalization with optimal results. DEN guided-probing demonstrated high success rates in cases with an earlier failed probing. Available dacryoendoscopes allow high-quality image capture (15,000 pixels) with multiple ports for additional instrumentation and irrigation. Dacryoendoscopic examination of canaliculus and nasolacrimal duct plays a significant role in the diagnosis and management of lacrimal disorders. Further improvements in microendoscopic techniques and instrumentation will expand its clinical usage and give impetus to minimally invasive lacrimal surgeries.Dacryoendoscopy examinations are increasingly playing a significant role in the diagnosis and therapies of lacrimal drainage disorders.


High in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical Neisseria gonorrhoeae isolates from 21 European countries from 2012 to 2014.
Resistance in Neisseria gonorrhoeae against all antimicrobials available for the treatment of gonorrhea has emerged. The first gonococcal strains with high-level resistance to ceftriaxone, the last option for first-line empirical antimicrobial monotherapy, were recently described. Consequently, new treatment options are essential. In this study, the in vitro activity of the novel spiropyrimidinetrione ETX0914 (AZD0914), a DNA topoisomerase II inhibitor, was investigated among contemporary consecutive clinical N. gonorrhoeae isolates obtained in 21 European countries and compared to the activities of antimicrobials currently or previously recommended for treatment. Consecutive clinical N. gonorrhoeae isolates (n = 873) cultured in 21 European countries from 2012 to 2014 were examined for their susceptibility to ETX0914. The MICs of ETX0914 were determined using the agar dilution method. For comparison, the MICs of ceftriaxone, cefixime, azithromycin, and ciprofloxacin were determined using Etest or the agar dilution method. For ETX0914, the MIC range, modal MIC, MIC50, and MIC90 were ≤0.002 to 0.25 mg/liter, 0.125 mg/liter, 0.064 mg/liter, and 0.125 mg/liter, respectively. The MIC values were substantially lower than those of the fluoroquinolone ciprofloxacin and most other antimicrobials examined. No cross-resistance with any other examined antimicrobial was observed. In conclusion, the in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical isolates from 21 European countries was high, and no cross-resistance to antimicrobials currently or previously used for gonorrhea treatment was indicated. Additional studies investigating the in vitro and in vivo induction and mechanisms of ETX0914 resistance in gonococci, pharmacokinetics/pharmacodynamics in modeling/simulations and in humans, and performance in randomized controlled gonorrhea treatment trials are essential.


Hyperestrogenism and low serum testosterone-17β-estradiol ratio are associated with non-bacterial male accessory gland inflammation.
This study evaluated the serum concentrations of the main sex hormones in selected patients with non-bacterial male accessory gland infection (MAGI). The results suggest that the mean serum concentrations of 17β-estradiol (method : chemiluminescence) in these patients are significantly higher compared to the controls (55.0 ± 15.0 vs. 26.5 ± 12.0 pg/mL; P <0.05) and the percentage of patients with MAGI and associated hyperestrogenism (according to the laboratory range used in this study) was significantly higher (25.00% vs. 3.00%; P <0.05). Moreover, the percentage of patients with non-bacterial MAGI and associated testosterone deficiency (serum total testosterone <2.49 ng/mL) was significantly higher (18.00% vs. 2.00%; P <0.05). Finally, patients with non-bacterial MAGI showed a significantly lower total testosterone-17β-estradiol ratio compared to the controls (72.7 vs. 173.0; P <0.05). The results of this study, with some limitations (in particular the method applied for the determination of serum concentrations of 17β-estradiol) represent in our opinion, a topic worthy of further investigation for a correct endocrinological characterization of these patients, useful for clinical practice.


Supplementation with Docosahexaenoic Acid and Extra Virgin Olive Oil Prevents Liver Steatosis Induced by a High-Fat Diet in Mice through PPAR-α and Nrf2 Upregulation with Concomitant SREBP-1c and NF-kB Downregulation.
Nonalcoholic fatty liver disease is the most common cause of liver disease, for which there is no validated drug therapy at present time. In this respect, the PUFA docosahexaenoic acid (DHA; C22:6 n-3) modulate lipid metabolism in the liver, and extra virgin olive oil (EVOO) has hepatoprotective effects. The effect of combined DHA (C22:6 n-3) and EVOO administration to mice on oxidative stress and metabolic disturbances induced by high-fat diet (HFD) is evaluated. Male C57BL/6J mice are fed with a control diet (10% fat, 20% protein, and 70% carbohydrates) or an HFD (60% fat, 20% protein, and 20% carbohydrates) for 12 weeks. Animals are supplemented with DHA (50 mg/kg/day), EVOO (50 mg/kg/day), or DHA + EVOO through oral route. DHA + EVOO cosupplementation results in greater protection (p < 0.05) over that elicited by DHA or EVOO supply alone, when compared to the damage induced by HFD. DHA + EVOO significantly reduces hepatic steatosis, oxidative stress, systemic inflammation, and insulin resistance. Synergistic beneficial effects of DHA + EVOO supplementation are associated with the activation/inactivation of key transcription factors involved in the above-mentioned processes. Data presented indicate that dietary supplementation with DHA + EVOO drastically reduces the development of nonalcoholic fatty liver disease.


[Australian Medical Sheepskin for prevention of pressure ulcers: individual patient data meta-analysis shows effectiveness].
To assess the effectiveness of the Australian Medical Sheepskin (AMS) on the prevention of sacral pressure ulcers based on combined data from 3 previously published trials. Meta-analysis of randomised clinical trials (RCTs). The effectiveness of these specially treated sheepskins from the Merino sheep was studied in three RCT's (2 involving Australian hospital patients and 1 involving Dutch nursing-home patients). In all 3 trials patients were randomized to 1 of 2 groups: a control group, who received standard care, and an intervention group, who, in addition to standard care, had at least one AMS placed under the sacral area when in bed. The total research population consisted of 1,281 patients from 11 institutions with 45 nursing wards. Data from the 3 RCT's were pooled and analysed: (a) with conventional meta-analysis based on the published effect sizes and (b) with multilevel logistic regression analysis based on the combined individual patient data for each trial separately and for the combined dataset. The primary outcome measure was the incidence of sacral pressure ulcers. The incidence of sacral pressure ulcers was 12.2% in the control group versus 5.4% in the intervention group. The odds-ratio was 0.37 (95% CI: 0.17-0.77) with conventional meta-analysis, and 0.35 (95% CI: 0.23-0.55) with multilevel logistic regression analysis on the combined individual patient data. Both analysis methods confirm that the AMS is effective in preventing sacral pressure ulcers. The confidence interval in the multilevel logistic regression analysis on individual patient data was almost 50% smaller than in the conventional meta-analysis, and gave a more reliable picture of the actual effect.


Purification of an autoantigenic 75-kDa human melanosomal glycoprotein.
Only a few autoantigenic human tumor antigens have been purified and characterized. We employed the monoclonal antibody (MAb) TA99 to isolate, purify and partially characterize an autoantigenic intracellular glycoprotein, gp75, from human melanoma cells. The gp75 antigen is the most abundant glycoprotein expressed in human melanocytes and pigmented melanomas and is the human homologue of the mouse brown locus gene product. Differential solubilization of melanoma membrane fraction and subcellular fractionation of pigmented melanoma cells showed that gp75 is an integral membrane protein localized to melanosomes. The gp75 glycoprotein eluted as a broad peak during ion exchange chromatography and appeared as a protein with broad pI (pI 5.5-5.9), consistent with charge microheterogeneity. gp75 also exhibited heterogeneity of binding to concanavalin A. Tyrosine hydroxylase (tyrosinase) activity co-purified with gp75 during membrane solubilization and anion exchange and Con A chromatography. However, most tyrosine hydroxylase activity could be dissociated from gp75 antigen during MAb TA99 affinity chromatography. TA99 did not immunoprecipitate or deplete tyrosine hydroxylase activity from lysates of human melanoma cells. Attempts to obtain N-terminal amino acid sequence of purified gp75 were not successful due to blocked N-terminus. Amino acid composition of gp75 was similar to that of tyrosinase. Physicochemical similarities and limited identity in the primary structure between gp75 and tyrosinase support the conclusion that the gp75 antigen does not exhibit tyrosine hydroxylase activity, but is a member of a tyrosinase-related family of proteins.


[Thyroid pathology of newborn infants of mothers with Basedow's disease].
Of 15 neonates born to mothers presenting with Graves' disease, who were admitted for presumptive thyroid disorder, 6 presented with neonatal thyrotoxicosis, 4 with goiter and/or hypothyroidism, and 5 presented with euthyroidism. In cases with thyrotoxicosis, the mothers were not or insufficiently treated. Evolution was regressive in 5 instances, there was a craniostenosis and persisting hyperthyroidism in one case. In cases with goiter and/or hypothyroidism, on the other hand, the mothers were correctly treated, and neonatal manifestations were benign and transient. This emphasizes both the importance of supervising gravidic hyperthyroidism and the complexity of materno-foetal relationship in thyroid diseases.